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Abstract Background Bacterial pneumonia is one of the most common causes of acute respiratory distress syndrome. In fulminant cases, when mechanical ventilation fails, veno-venous extracorporeal membrane oxygenation is required. However, this method is still associated with significant mortality and a wide range of potential complications. However, there are now many case reports of good outcomes even in patients with prolonged extracorporeal oxygenation, as in our rather complicated case report. Case presentation Our case report describes a complicated but successful treatment of a severe, devastating bacterial pneumonia in a 39-year-old European polymorbid woman with a rare form of diabetes mellitus, which had been poorly compensated for a long time with limited compliance, in the context of a combined immunodeficiency that strongly influenced the course of the disease. The patient’s hospitalization required a total of 30 days of veno-venous extracorporeal membrane oxygenation therapy and more than 50 days of mechanical ventilation. Numerous complications, particularly bleeding, required seven chest drains, two extracorporeal membrane oxygenation circuit changes, and one surgical revision. The patient’s mental state required repeated psychiatric intervention. Conclusion It is possible that even the initially severely damaged lung parenchyma can develop its regenerative potential if suitable conditions are provided for this process, including a sufficiently long period of extracorporeal membrane oxygenation. We believe that this case report may also contribute to the consideration of the indications and contraindications of extracorporeal support. The authors also discuss the limitations and risks of prolonged veno-venous extracorporeal membrane oxygenation support and periprocedural anticoagulation strategies.

The article deals with the possible application of the Solver optimization module to solving the single-circuit transport problems. First, the article describes the single-circuit transport problems and the optimization module Solver itself. Using the specific model example of beer distribution, the author demonstrates the algorithm which may be applied to solving single-circuit transport problems by means of Solver. The travel route designed by Solver is then compared with the originally proposed route. The values being compared include the total length of travel routes created and the associated variable costs spent on serving customers and also route design time. Thus, using the practical example of beer distribution, the manuscript has demonstrated the algorithm which is used for addressing the single-circuit transport problems. Nonetheless, possible application of the Solver tool is not limited to seeking a solution to the travelling salesman problem only. It can also be implemented even to discussing the multi-circuit transport problems with various confinements.

Cell cycle progression is driven by the coordinated regulation of the activities of cyclin-dependent kinases (Cdks). Of the several mechanisms known to regulate Cdk activity in response to external signals, regulation of cyclin gene expression, post-translational modification of Cdks by phosphorylation-dephosphorylation cascades, and the interaction of cyclin/Cdk complexes with protein inhibitors have been thoroughly studied. During recent years, much attention has also been given to mechanisms that regulate protein degradation by the ubiquitin/proteasome pathway, as well as to the regulation of subcellular localization of the proteins that comprise the intrinsic cell cycle clock. The purpose of the present review is to summarize the most important aspects of the various mechanisms implicated in cell cycle regulation. [ABSTRACT FROM AUTHOR]

The aim of this paper is to familiarize readers with several telematic systems that may be observed on the Czech railway network. In order to function correctly, they use special technical devices for detecting positions of trains and their tracking. In the introductory part, a brief overview of individual ways of train detecting and tracking in the Czech Republic is given, which is then followed by a detailed description of the related telematic systems, including the principles of their functioning and graphic presentation of their practical use. The paper also contains demonstrative photo documentation and schematic illustrations of principles of functioning of the discussed systems.

Abstract Background Significance analysis at single gene level may suffer from the limited number of samples and experimental noise that can severely limit the power of the chosen statistical test. This problem is typically approached by applying post hoc corrections to control the false discovery rate, without taking into account prior biological knowledge. Pathway or gene ontology analysis can provide an alternative way to relax the significance threshold applied to single genes and may lead to a better biological interpretation. Results Here we propose a new analysis method based on the study of networks of pathways. These networks are reconstructed considering both the significance of single pathways (network nodes) and the intersection between them (links). We apply this method for the reconstruction of networks of pathways to two gene expression datasets: the first one obtained from a c-Myc rat fibroblast cell line expressing a conditional Myc-estrogen receptor oncoprotein; the second one obtained from the comparison of Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia derived from bone marrow samples. Conclusion Our method extends statistical models that have been recently adopted for the significance analysis of functional groups of genes to infer links between these groups. We show that groups of genes at the interface between different pathways can be considered as relevant even if the pathways they belong to are not significant by themselves.

Abstract Time course gene expression experiments are a popular means to infer co-expression. Many methods have been proposed to cluster genes or to build networks based on similarity measures of their expression dynamics. In this paper we apply a correlation based approach to network reconstruction to three datasets of time series gene expression following system perturbation: 1) Conditional, Tamoxifen dependent, activation of the cMyc proto-oncogene in rat fibroblast; 2) Genomic response to nutrition changes in D. melanogaster; 3) Patterns of gene activity as a consequence of ageing occurring over a life-span time series (25y–90y) sampled from T-cells of human donors. We show that the three datasets undergo similar transitions from an "uncorrelated" regime to a positively or negatively correlated one that is symptomatic of a shift from a "ground" or "basal" state to a "polarized" state. In addition, we show that a similar transition is conserved at the pathway level, and that this information can be used for the construction of "meta-networks" where it is possible to assess new relations among functionally distant sets of molecular functions.

Aging-associated inflammation, or 'inflammaging" is a driver of multiple age-associated diseases. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that functions to activate interferon response upon detecting viral DNA in the cytoplasm. cGAS contributes to inflammaging by responding to endogenous signals such as damaged DNA or LINE1 (L1) cDNA which forms in aged cells. While cGAS knockout mice are viable their aging has not been examined. Unexpectedly, we found that cGAS knockout mice exhibit accelerated aging phenotype associated with induction of inflammation. Transcription of L1 elements was increased in both cGAS knockout mice and in cGAS siRNA knockdown cells associated with high levels of cytoplasmic L1 DNA and expression of ORF1 protein. Cells from cGAS knockout mice showed increased chromatin accessibility and decreased DNA methylation on L1 transposons. Stimulated emission depletion microscopy (STED) showed that cGAS forms nuclear condensates that co-localize with H3K9me3 heterochromatin marks, and H3K9me3 pattern is disrupted in cGAS knockout cells. Taken together these results suggest a previously undescribed role for cGAS in maintaining heterochromatin on transposable elements. We propose that loss of cGAS leads to loss of chromatin organization, de-repression of transposable elements and induction of inflammation resulting in accelerated aging.

To explore associations between histoplasmosis and race and ethnicity, socioeconomic status, and rurality, we conducted an in-depth analysis of social determinants of health and histoplasmosis in 8 US states. Using the Minority Health Social Vulnerability Index (MH SVI), we analyzed county-level histoplasmosis incidence (cases/100,000 population) from the 8 states by applying generalized linear mixed hurdle models. We found that histoplasmosis incidence was higher in counties with limited healthcare infrastructure and access as measured by the MH SVI and in more rural counties. Other social determinants of health measured by the MH SVI tool either were not significantly or were inconsistently associated with histoplasmosis incidence. Increased awareness of histoplasmosis, more accessible diagnostic tests, and investment in rural health services could address histoplasmosis-related health disparities.

Coccidioidomycosis, histoplasmosis, and blastomycosis are lower respiratory tract fungal infections whose signs and symptoms can resemble those of other respiratory illnesses, including pneumonia caused by bacterial or viral etiologies; this overlap in clinical presentation might lead to missed or delayed diagnoses. The causative fungi live in the environment, often in soil or plant matter. To describe the epidemiologic characteristics of cases of coccidioidomycosis, histoplasmosis, and blastomycosis during the COVID-19 pandemic, CDC analyzed case surveillance data for 2019-2021. During this period, a total of 59,655 coccidioidomycosis cases, 3,595 histoplasmosis cases, and 719 blastomycosis cases were reported to CDC. In 2020, fewer cases of each disease occurred in spring compared with other seasons, and most cases occurred in fall; national seasonality is not typically observed, and cases were seasonally distributed more evenly in 2019 and 2021. Fewer cases coinciding with the start of the COVID-19 pandemic, along with an unusually high blastomycosis case fatality rate in 2021 (17% compared with more typical rates of 8%-10%), suggest that the pandemic might have affected patients' health care-seeking behavior, public health reporting practices, or clinical management of these diseases. Increased awareness and education are needed to encourage health care providers to consider fungal diseases and to identify pneumonia of fungal etiology. Standardized diagnostic guidance and informational resources for fungal testing could be incorporated into broader respiratory disease awareness and preparedness efforts to improve early diagnosis of coccidioidomycosis, histoplasmosis, and blastomycosis., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

In November 2022 the first Dark Genome Symposium was held in Boston, USA. The meeting was hosted by Rome Therapeutics and Enara Bio, two biotechnology companies working on translating our growing understanding of this vast genetic landscape into therapies for human disease. The spirit and ambition of the meeting was one of shared knowledge, looking to strengthen the network of researchers engaged in the field. The meeting opened with a welcome from Rosana Kapeller and Kevin Pojasek followed by a first session of field defining talks from key academics in the space. A series of panels, bringing together academia and industry views, were then convened covering a wide range of pertinent topics. Finally, Richard Young and David Ting gave their views on the future direction and promise for patient impact inherent in the growing understanding of the Dark Genome., (© 2023. The Author(s).)

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a 12-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age., Competing Interests: BB, KM, ES, EM, YC, NT, YL, LS, TK, AK, PB, ZQ, PC, PD, DT, Fd, BC, JS, GK No competing interests declared, (© 2023, Baggett, Murphy, Sengun et al.)

Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Patients receiving eculizumab have an increased risk for meningococcal disease, but most reported cases are attributable to encapsulated meningococcal strains. We describe a case in which a nongroupable meningococcal strain, which rarely causes disease in healthy persons, caused fatal disease in an eculizumab recipient despite meningococcal vaccination.

Non-pathogenic Bacillus species used in cleaning products produce the appropriate enzymes to degrade stains and soils. However, there is little scientific data regarding the human exposure by inhalation of Bacillus spores during or after use of microbial-based cleaning products. Herein, air samples were collected at various locations in a ventilated, carpeted, residential room to determine the air concentration of viable bacteria and spores during and after the application of microbial-based carpet cleaning products containing Bacillus spores. The influence of human activities and vacuuming was investigated. Bioaerosol levels associated with use and post-application activities of whole room carpet treatments were elevated during post-application activity, but quickly returned to the indoor background range. Use of trigger spray spot applications generated aerosolized spores in the immediate vicinity, however, their use pattern and the generation of mostly non-respirable particles suggest minimal risks for pulmonary exposure from their use. The aerosol counts associated with use of these microbial-based cleaners were below the recommendation for safe exposure levels to non-pathogenic and non-toxigenic microorganisms except during application of the spot cleaner. The data presented suggest that carpet cleaning products, containing non-pathogenic Bacillus spores present a low potential for inhalation exposure and consequently minimal risk of adverse effects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities., (Copyright © 2017 Elsevier Inc. All rights reserved.)